Advanced malignant diseases such as castration-resistant prostate cancer (CRPC) are difficult to manage because these cancers tend to metastasize and are often poorly responsive to the standard chemotherapy. RNA-interference (RNAi) therapeutics, e.g. small-interfering RNAs (siRNAs), hold high potential for silencing critical molecular pathways to restore the cancer chemosensitivity and slow down the spread of cancer. Our group has recently developed a new generation of hybrid nanotechnology, represented by lipid-polymer hybrid nanocarrier (LPN), to provide sustained, controlled intracellular siRNA supply efficiently at low normal tissue toxicity. Using LPN for anti-survivin-siRNA delivery, we reported significant RNAi-chemosensitization in vitro and in vivo for extended time. Our results further demonstrated that by silencing survivin, we were able to substantially suppress the metastatic potential of CRPC. LPN-integrated RNAi-therapy therefore may simultaneously tackle the two most devastating problems of advanced CRPC. In this application, this promising therapy will be implemented using a cancer-surface targeting LPN. Specifically, we will (1) evaluate the in vivo tumor-targeting capabilities and pharmacokinetic properties of LPN in an orthotopic model of metastatic CRPC; (2) study the pharmacodynamic and therapeutic properties of LPN carrying anti-survivin siRNA for optimal CRPC chemosensitization and control of metastasis; (3) evaluate the therapeutic outcomes of chemo-RNAi combination therapy consisting of docetaxel and LPN carrying anti-survivin siRNA for CRPC treatment. Relevance to Public Health. Successful completion of this project will validate and optimize a nanotechnology-integrated RNAi-therapy for preventing advanced-stage cancers from spreading to the healthy tissues, and turning these often non-responsive cancers responsive to the standard drug treatment again. PUBLIC HEALTH RELEVANCE: This project will study the use of a smart nanocarrier (small device about the size of one millionth of a millimeter) to recognize the prostate cancer cells that have become highly resistant to standard drug treatment and are prone to spreading around in the body. Once reached the cancer target, this nanocarrier is able to steadily and efficiently deliver a novel genetic material to shut down a molecular pathway in the cancer that is critical for its drug-resistant and aggressive behaviors. Successful completion of this project may turn the tough-to-treat prostate cancer treatable again and prevent this aggressive cancer from invading the healthy body tissues.